title: Uptake and intracellular trafficking of superantigens in dendritic cells.
abstract: Bacterial superantigens (SAgs) are exotoxins produced mainly by Staphylococcus aureus and Streptococcus pyogenes that can cause toxic shock syndrome (TSS). According to current paradigm, SAgs interact directly and simultaneously with T cell receptor (TCR) on the T cell and MHC class II (MHC-II) on the antigen-presenting cell (APC), thereby circumventing intracellular processing to trigger T cell activation. Dendritic cells (DCs) are professional APCs that coat nearly all body surfaces and are the most probable candidate to interact with SAgs. We demonstrate that SAgs are taken up by mouse DCs without triggering DC maturation. SAgs were found in intracellular acidic compartment of DCs as biologically active molecules. Moreover, SAgs co-localized with EEA1, RAB-7 and LAMP-2, at different times, and were then recycled to the cell membrane. DCs loaded with SAgs are capable of triggering in vitro lymphocyte proliferation and, injected into mice, stimulate T cells bearing the proper TCR in draining lymph nodes. Transportation and trafficking of SAgs in DCs might increase the local concentration of these exotoxins where they will produce the highest effect by promoting their encounter with both MHC-II and TCR in lymph nodes, and may explain how just a few SAg molecules can induce the severe pathology associated with TSS.
authors.affiliation: Instituto de Estudios de la Inmunidad Humoral (IDEHU), CONICET-UBA, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: María B
authors.initials: MB
authors.lastname: Ganem
authors.forename: Mauricio C
authors.initials: MC
authors.lastname: De Marzi
authors.forename: María J
authors.initials: MJ
authors.lastname: Fernández-Lynch
authors.forename: Carolina
authors.initials: C
authors.lastname: Jancic
authors.forename: Mónica
authors.initials: M
authors.lastname: Vermeulen
authors.forename: Jorge
authors.initials: J
authors.lastname: Geffner
authors.forename: Roy A
authors.initials: RA
authors.lastname: Mariuzza
authors.forename: Marisa M
authors.initials: MM
authors.lastname: Fernández
authors.forename: Emilio L
authors.initials: EL
authors.lastname: Malchiodi
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D004768:Enterotoxins / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D018089:Superantigens / Q000276:immunology / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000942:Antigens, Bacterial; D004768:Enterotoxins; D052119:Lysosomal-Associated Membrane Protein 2; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C109168:T-cell receptor Vbeta 8.2; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C419397:enterotoxin G, staphylococcal; C419398:enterotoxin I, staphylococcal; D000090802:rab7 GTP-Binding Proteins; C117321:streptococcal superantigen SSA; D020691:rab GTP-Binding Proteins